RP-3: Targeting oncogenic pathways in genetically complex sarcomas ABSTRACT Our overall goal is to find effective targeted therapies for two of the most common and aggressive types of genetically complex sarcomas: myxofibrosarcoma (MFS) and undifferentiated pleomorphic sarcoma (UPS). The development of new targeted therapies is urgent and vital for improving outcomes of these patients. However, the complexity of alterations in these sarcomas has made it difficult to find the true drivers of oncogenesis. We found that high expression of ITGA10 (integrin-?10) in MFS and UPS drives sarcomagenesis by activating RAC/PAK and PI3K/mTOR signaling, and that 85% of MFS and UPS harbor alterations that can activate the PI3K/mTOR signaling cascade. Signaling in this cascade stimulates protein translation, and our preliminary results suggest that MFS and UPS, as well as dedifferentiated liposarcoma (DDLS), rely on oncogenic translation enabled by the RNA helicase eIF4A. We therefore hypothesize that most MFS/UPS will be dependent on PI3K/mTOR signaling and eIF4A for growth and survival. First, we plan to define the role of the PI3K/mTOR and MAPK pathway activation in sarcomagenesis and identify molecular alterations that associate with outcome. Second, we plan to determine the efficacy of mTOR, PI3K, and MEK inhibitors in MFS/UPS cell lines, xenografts and PDX models. In preliminary data the PI3K/mTOR inhibitors alone led to feedback upregulation of the MAPK pathway, which could cause adaptive resistance to therapy. Therefore, we will test combining each of the PI3K and mTOR inhibitors with a MEK inhibitor, to test whether the combination blocks the adaptive response and leads to synergistic suppression of MFS/UPS. Third, we will determine the efficacy and mechanism of action of a new eIF4A inhibitor, CR31B, in MFS, UPS, and DDLS cell lines and xenografts. To discover which mRNAs require eIF4A for their translation in these cell lines, we will perform ribosome footprinting on CR31B-treated cells. We expect that mTOR, PI3K, and eIF4A inhibitors will be effective therapy in the majority of MFS and UPS. Clarification of the roles of the PI3K/mTOR and oncogenic translation pathways will elucidate mechanisms of tumorigenesis and metastasis, identify new drug targets, identify effective combination therapies, and enable precision oncology. We expect that at least one of the treatment strategies investigated in this proposal will lead to clinical trials for patients with MFS and UPS.